Comparison of noninvasive cardiac output and stroke volume measurements using electrical impedance tomography with invasive methods in a swine model

Pulmonary artery catheterization (PAC) has been used as a clinical standard for cardiac output (CO) measurements on humans. On animals, however, an ultrasonic flow sensor (UFS) placed around the ascending aorta or pulmonary artery can measure CO and stroke volume (SV) more accurately. The objective of this paper is to compare CO and SV measurements using a noninvasive electrical impedance tomography (EIT) device and three invasive devices using UFS, PAC-CCO (continuous CO) and arterial pressure-based CO (APCO). Thirty-two pigs were anesthetized and mechanically ventilated. A UFS was placed around the pulmonary artery through thoracotomy in 11 of them, while the EIT, PAC-CCO and APCO devices were used on all of them. Afterload and contractility were changed pharmacologically, while preload was changed through bleeding and injection of fluid or blood. Twenty-three pigs completed the experiment. Among 23, the UFS was used on 7 pigs around the pulmonary artery. The percentage error (PE) between COUFS and COEIT was 26.1%, and the 10-min concordance was 92.5%. Between SVUFS and SVEIT, the PE was 24.8%, and the 10-min concordance was 94.2%. On analyzing the data from all 23 pigs, the PE between time-delay-adjusted COPAC-CCO and COEIT was 34.6%, and the 10-min concordance was 81.1%. Our results suggest that the performance of the EIT device in measuring dynamic changes of CO and SV on mechanically-ventilated pigs under different cardiac preload, afterload and contractility conditions is at least comparable to that of the PAC-CCO device. Clinical studies are needed to evaluate the utility of the EIT device as a noninvasive hemodynamic monitoring tool.


S1. Protocol of the first study
We began each experiment with a baseline/stabilization part where MAP was stably maintained for at least 5 minutes.This baseline/stabilization part was repeated after each intervention.The part #1 was to measure CO and SV under different afterload conditions using the following protocol: 1. Nitroprusside was slowly administered while increasing its dose until MAP decreased to 60 mmHg.The dose was maintained for 15 minutes.
3. Phenylephrine was slowly administered while increasing its dose until MAP increased above 85 mmHg.The dose was maintained for 15 minutes.4. Waited until MAP returned to 70~80 mmHg.Further waited for 5 minutes.
The part #2 was to measure CO and SV under different contractility conditions as follows: 1. Dobutamine was slowly administered while increasing its dose until MAP increased above 100 mmHg.The dose was maintained for 5 minutes.
2. Waited until MAP returned to 70~80 mmHg.When MAP did not return to 70~80 mmHg, crystalloid fluid (Plasma Solution-A Injection, CJ Healthcare, Korea) was administered until MAP returned to 70~80 mmHg.Waited for 5 minutes.
3. Esmolol was slowly administered while increasing its dose until MAP decreased below 60 mmHg.The dose was maintained for 15 minutes.4. Waited until MAP returned to 70~80 mmHg for 30 minutes.
The part #3 was to measure CO and SV under different preload conditions as follows: 1. Blood was withdrawn from the animal through a needle, which was inserted into a blood vessel and connected to a blood bag, until MAP decreased below 50 mmHg.The amount of blood withdrawn and the bleeding rate varied in different animals.
2. Waited for 5 minutes without withdrawing additional blood.

S2. Protocol of the second study
We began each experiment with a baseline/stabilization part where MAP was stably maintained for at least 5 minutes.This baseline/stabilization part was repeated after each intervention.The part #1 was the same as the part #1 of the first study.
The part #2 was the same as the part #2 of the first study.
The part #3 was to measure CO and SV under different afterload conditions using the following protocol: 1. Thromboxane was slowly administered while increasing its dose until the mean PAP increased to 35 mmHg.The dose was maintained for 5 minutes.
2. Waited until the mean PAP returned to 25 mmHg.Further waited for 5 minutes.
The part #4 was to measure CO and SV under different preload conditions as follows: 1. Blood was withdrawn from the animal through a needle, which was inserted into a blood vessel and connected to a blood bag, until MAP decreased below 50 mmHg.The total amount of blood withdrawn and the bleeding rate varied in different animals.
2. Waited for 5 minutes without withdrawing additional blood.
3. The removed blood was transfused into the pig for 5 to 10 minutes.When MAP decreased below 50 mmHg during fluid administration, dobutamine was administered until MAP increased above 50 mmHg.

S3. Thoracotomy procedure
Each pig was placed on an operating table in the right lateral position.Thoracotomy started at the 5 th or 6 th intercostal space.Subcutaneous tissues, muscles and pleura were dissected using an electrosurgical unit (ESU).Then, a retractor was placed between the ribs to secure a view to install the C-shaped UFS around the pulmonary artery while the pericardium was open.There was little displacement of the heart during this thoracotomy procedure.After checking the signal from the installed UFS around the pulmonary artery, the dissected layers were sutured and wound areas were taped to close the chest.Then, we attached 16 sensing electrodes and 1 reference electrode for EIT measurements around the chest.We did not observe any noticeable changes in the acquired signals before and after the thoracotomy procedure.We believe that the thoracotomy did not affect the PAC-CCO, APCO and EIT measurements per se.

S4. EIT data collection method
The EIT device injected current between a chosen neighboring electrode pair.For each current injection, 16 voltage data were measured simultaneously (parallel measurements).13 of them were used for SV/CO calculations and 3 were used to estimate electrode-skin contact impedance values.This was repeated for all 16 neighboring current-injecting electrode pairs in 10 ms.

S5. Percentage error and concordance
To compute the percentage error (PE), we let X ,  and X ,  be the jth data from the ith animal using the reference device and the device under test, respectively.The number of data pairs from the th animal is   and the number of animals is .Then, the total number of data pairs is  = ∑    =1 . Denoting the difference as  , ≔ X ,  X ,  , we compute the PE as follows: where and and  ℎ is the harmonic mean of {  } =1  .Here,  ̂ is the standard deviation of the difference accounting for inter-subject biases.
The condition of concordance in measured data X DEV1 and X DEV2 by the DEV1 and DEV2 was defined as follows: where ∆X DEV1 () and ∆X DEV2 () are the percentage difference in X DEV1 and X DEV2 at time i, respectively, as follows: and where ( 1) and  are two consecutive time points when the entire experiment time was divided into non-overlapping 10-min intervals.Similarly, the condition of discordance in measurements X was defined as The concordance of X denoted as CCD X was computed as the percentage of data pairs satisfying the concordance condition outside an exclusion band of 15% in both ∆X DEV1 and ∆X DEV2 as follows: where # denotes the number of elements contained in the set ,   is the set of data pairs in the exclusion band,   is the set of data pairs satisfying the concordance condition, and   is the set of data pairs satisfying the discordance condition.The sets were defined as

S9. Details about Bland-Altman and Concordance Analyses
Table S2.Details of the Bland-Altman analyses.The results for the APCO method should not be interpreted conclusively due to its unreliability in animals.
3. 1 L of crystalloid fluid (Plasma Solution-A Injection, CJ Healthcare, Korea) was intravenously administered for 20 minutes.When MAP decreased below 50 mmHg during fluid administration, dobutamine was administered until MAP increased above 50 mmHg.4. Waited for about 20 minutes.

Fig
Fig. S1(a) shows an example of the EIT device's 208-channel impedance signals from an animal Fig. S2.(a) Example of the CVS extracted from the 208-channel impedance data shown in Fig. S1 using the leadforming algorithm 25 .(b) Power spectrum of the CVS in (a) shows a fundamental frequency of about 1.2 Hz corresponding to a heart rate of about 72 bpm.

S7.
Fig. S3.(a)~(p) Measured CO, SV, COScaled, SVScaled, HR, ABP, CVP and PAP data for 16 pigsfrom the first study.In the CO and SV plots, neither amplitude scaling nor time-delay adjustment was applied.In the COScaled and SVScaled plots, the EIT and APCO data were scaled in amplitude using a PAC-CCO datum in the beginning of each experiment as a reference value, and a timedelay adjustment was applied to the PAC-CCO data.The mean values of the ABP, CVP and PAP data are shown in yellow.SV plots were smoothed to remove short-term SV variations.
Fig. S4.(a)~(g) Measured CO, SV, COScaled, SVScaled, HR, ABP, CVP and PAP data for 7 pigsfrom the second study.In the CO and SV plots, neither amplitude scaling nor time-delay adjustment was applied.In the COScaled and SVScaled plots, the EIT, PAC-CCO and APCO data were scaled using a UFS datum in the beginning of each experiment as a reference value, and a time-delay adjustment was applied to the PAC-CCO data.The mean values of the ABP, CVP and PAP data are shown in yellow.SV plots were smoothed to remove short-term SV variations.

Table S3 .
Details of the concordance analyses.The results for the APCO method should not be interpreted conclusively due to its unreliability in animals.